Every year, millions of people are born with debilitating genetic disorders, a result of inheriting just one faulty gene from their parents. They may have been dealt a dud genetic hand, but they do not have to stick with it. With the power of modern genetics, scientists are developing ways of editing these genetic errors and reversing the course of many hard-to-treat diseases.

These gene therapies exploit the abilities of viruses – biological machines that are already superb at penetrating cells and importing genes. By removing their ability to reproduce, and loading them with the genes of our choice, we can transform viruses from causes of disease into vectors for cures.

After a few shaky starts, some of these approaches are beginning to hit their stride. Thirteen children with SCID, an immune disorder that leaves people fatally vulnerable to infections, now have working immune systems. Several British patients with haemophilia, which prevents their blood from clotting properly, can now produce a clotting protein called factor IX, which they once had to inject. A British man and three Americans with inherited forms of progressive blindness can see again.

It is still early days as far as trumpeting gene therapy cures are concerned, but even if they do succeed there is still one significant limitation that cannot be overlooked. Treating adults and children in this way will do for some disorders, but genetic disorders cause irreparable organ damage, or even death, very early. “With some of the diseases that we look at, five years old is too late. Sometimes, you don’t get to the age of five,” says Simon Waddington from University College London. “Every single one is a little bit niche but when you list them all out, there’s quite a lot of them.”

To treat such conditions, we need to intervene as early as possible, and this means correcting genetic disorders in the womb. There are advantages to such “prenatal gene therapy”. Organs that are hard to target after birth, such as airways blocked with mucus in cystic fibrosis patients, may be easier to reach in the womb. Being smaller, foetuses need a relatively smaller amount of delivery vector. And their immune systems are naive, so they are unlikely to mount an immune response to these vectors.

Risk assessment

So far, several teams have tested prenatal gene therapy in animals, including mice, monkeys and sheep. The results have been promising. In several cases, the animals produce decent levels of foreign proteins for many months, and their immune systems tolerate the added genes. Some have even been cured of their diseases.

Despite these successes, the research has reached an impasse. No one has tried prenatal gene therapy in humans, and no clinical trials are in the works. This is understandable. Altering a foetus’ genes is a sombre prospect, especially as gene therapy is still a relatively immature technology. “It hasn’t been embedded enough yet,” says Waddington. If these treatments can prove their safety and effectiveness in adults, the field will move towards trials in newborn babies, and from there to prenatal tests.

For now, there are still many potential risks to address. “We’re still very much looking at which is the right vector to use,” says Anna David, from University College London. Lentiviruses and retroviruses (such as HIV) shunt their genes into those of their host. They would seem to provide an ideal way of correcting a faulty gene, either by overwriting it, or providing a cell with working copies.

But if the viruses insert their DNA in the wrong place, they could disrupt other important genes, causing cancers or developmental problems. These fears are well-founded. Five of the twenty children with SCID, who took part in some of the first successful gene therapy trials, developed leukaemia as a result of their treatment.

Other groups of viruses, such as adeno-associated viruses (AAV), reputedly produce safer vectors, because they stay outside their host’s genome without inserting their DNA. But they have their own disadvantages. As a foetus’ cells divide, the initial salvo of vectors becomes diluted out. That’s acceptable for slowly dividing tissues, like the nervous system, but it will not work in rapidly dividing tissues like bone marrow.

Once a vector is chosen, it must be guided to the right place. For bleeding disorders, it is a relatively simple matter of injecting the vectors into the bloodstream, via the umbilical cord. For diseases that affect more localised organs, ultrasound can help to guide a needle to the right spot.

As an alternative to injecting vectors directly into the womb, some scientists are looking to correct a foetus’ faulty genes outside of its body – by extracting cells, correcting the genes, and transplanting them back in again. “Then, you’re only targeting the cells that you want to target,” says David. She has already proved that this is possible in sheep, using transplanted cells that contained a simple marker gene. “The next step is to try and cure a genetic disease,” she says.

Case by case

But no matter what the approach, prenatal gene therapy will always involve taking blood samples from foetuses, and injecting vectors or cells back in. “There’s obviously a small miscarriage risk with that,” says Waddington. However, he points out that these injections are far less invasive than foetal surgeries and blood transfusions, which have been used to treat birth defects for several decades.

There is also a variable risk with the imported genes themselves. For example, factor IX clotting factor is not harmful at high levels, and people with haemophilia B already inject themselves with huge amounts of it. By contrast, genes that oversee large genetic networks could cause big problems if they are switched on in the wrong place, or at the wrong levels. In twoanimal studies, attempts to introduce growth factor genes into the lungs led to build-ups of abnormal tissue. There is also the possibility that the added genes could end up in the mother, via the placenta.

All of this means that every use of prenatal gene therapy has to be examined on a case-by-case basis. The technical challenges will vary depending on the organ being targeted, with each one having a different ideal vector, route of delivery or window of time. And as Waddington says, “You’ve got to look at the safety aspects for every single gene that you’re delivering.”

Target selection

This is why the first human trials of prenatal gene therapy, when they arrive, will probably involve a narrow range of diseases: those that are otherwise hard to treat, and that cause serious illness in foetuses or newborn babies. For example, babies with the severe form of Factor VII deficiency – a bleeding disorder – invariably start bleeding inside their heads, within hours or days after they are born. The results are fatal. Another blood disorder, alpha-thalassaemia major, kills foetuses before they are even born.

“I think it’s still not completely clear which diseases are the appropriate targets,” says Waddington. “But the feeling I get is that the diseases that are very nasty, very early, are the ones to go for.”

But most genetic disorders are not so clear-cut. Take Gaucher’s disease, a condition where abnormal fatty deposits build up in several organs, causing everything from weakened immune systems to early brain degeneration. It is caused by problems in one gene, but mutations can break the gene in 100 different ways, with varied consequences. Waddington has spent several years working on Gaucher’s and he says, “It’s quite clear that we don’t have a complete handle on the different signs and symptoms and the biochemical readouts of the disease. Some people may go downhill quickly while others surprise you and are relatively well at 10 years.”

Judy, yes, the intention is to only correct the one individual. In fact, one of the major concerns is that the virus could affect the “germline” – that’s the eggs and sperm that carry genetic information to the next generation. There are ethical issues about modifying an entire lineage rather than a person, and the risks are far greater too. If you’re treating an individual, you might get unintended genetic alterations (remember the cancer risk mentioned above). If the germline is similarly affected, those consequences could cascade down the generations.

Hi Natalie,
You make a valuable point, and one that we’ve often contemplated and also discussed with the PGD experts at University College London. PGD is not necessarily cheap and can be very arduous; Mums may sometimes go through several unsuccessful cycles. However PGD is available right now.
Nevertheless, postnatal gene therapy is showing promise in quite a wide range of inherited diseases including X-linked severe combined immune deficiency (SCID), ADA-SCID, X-linked adrenoleukodystrophy (famed in Lorenzo’s oil) inherited blindness, haemophilia, dyslipidemia and chronic granulomatous disease. However even in these cases, progression of the disease is halted, but it is not cured. Also, the adult immune system is still a major impediment to more widespread application. If a fetus was diagnosed in the womb with a severe genetic disease, then it may be better to use gene therapy as a prevention, because the disease may already have caused serious damage by the time of birth. Also, the fetal or neonatal immune system presents less of a barrier to successful gene delivery
I think that in utero gene transfer would provide an additional option, where postnatal gene therapy, PGD or termination were not desirable or possible.